NeuropeptideFF (FLFQPQRF-NH2) is an endogenous neuropeptide with morphine modulating activity. Neuropeptide FF (NPFF) immunoreactive nerve terminals and NPFF receptors were found to be highly localized in the superficial laminae of rat dorsal spinal cords. These observations strongly suggest a role for NPFF in the spinal cord function. In order to explore the functional role of NPFF, the secretion of NPFF from the rat spinal cord was studied. Furthermore, the possible effects of opiates on this NPFF release were also investigated. Substance P caused a release of NPFF from the spinal cord in a calcium dependent manner. Further studies with other substance P related peptides used as secretagogues indicated that a specific substance P receptor (SP-N) is involved in NPFF secretion from the spinal cord. In view of the role of substance P in sensory transmission, the results of this study strongly suggest a modulatory role for NPFF in antinociception. The study on the effect of morphine on NPFF efflux has demonstrated that naloxone can induce a release of NPFF from the spinal cord of rats pretreated with morphine. In contrast, naloxone was found to have nearly no effect on the basal efflux of NPFF. Other investigators have previously reported that NPFF administered ICV (third ventricle) into morphine-dependent rats can precipitate an opiate abstinence syndrome. Thus the results of this study strongly indicate that NPFF may be involved in naloxone precipitated abstinence syndrome in morphine dependent animals.